Abstract
Lysophosphatidic acid (LPA) is a bioactive lipid with activity in the nervous system mediated by G-protein-coupled receptors. Here, we examined the role of LPA signaling in the development of neuropathic pain by pharmacological and genetic approaches, including the use of mice lacking the LPA1 receptor. Wild-type animals with nerve injury develop behavioral allodynia and hyperalgesia paralleled by demyelination in the dorsal root and increased expression of both the protein kinase C γ-isoform within the spinal cord dorsal horn and the α2δ1 calcium channel subunit in dorsal root ganglia. Intrathecal injection of LPA induced behavioral, morphological and biochemical changes similar to those observed after nerve ligation. In contrast, mice lacking a single LPA receptor (LPA1, also known as EDG2) that activates the Rho–Rho kinase pathway do not develop signs of neuropathic pain after peripheral nerve injury. Inhibitors of Rho and Rho kinase also prevented these signs of neuropathic pain. These results imply that receptor-mediated LPA signaling is crucial in the initiation of neuropathic pain.
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Change history
20 June 2004
Replaced Figure 2c, corrected text
Notes
NOTE: In the version of this article initially published online, on p. 715, at the beginning of the second column, the antisense oligonucleotide was identified incorrectly. The first complete sentence of the column should begin, “Moreover, preinjury injection with LPA1 AS-ODN...” In addition, the bottom curve in Figure 2c was labeled incorrectly. The label should read “Wild-type”. These errors have been corrected for the HTML and print versions of the article.
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Acknowledgements
We thank T. Kawashima, S. Kondo, M. Matsumoto and T. Suematsu for technical help and behavioral studies, and S. Kozaki for BoTXC3. This study was supported by Special Coordination Funds of the Science and Technology Agency of the Japanese Government and Grants-in-Aid from the Ministry of Education, Science, Culture and Sports of Japan (H.U.) and by the National Institute of Mental Health, USA (J.C., J.J.C.).
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Supplementary Fig. 3
Schematic model showing role of LPA in development of neuropathic pain following peripheral nerve injury. (PDF 368 kb)
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Inoue, M., Rashid, M., Fujita, R. et al. Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling. Nat Med 10, 712–718 (2004). https://doi.org/10.1038/nm1060
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DOI: https://doi.org/10.1038/nm1060
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